Non-melanoma skin cancer (NMSCs) is the most common cancer in America, with over 2 million cases diagnosed annually. Despite the large population affected and resultant burden of disease, no effective chemopreventative strategies have been identified, especially among sun-damaged individuals with existing precancerous skin lesions who are at high risk of developing skin cancer. Actinic keratoses (AKs) are precancerous skin lesions that arise on sun-damaged skin and can progress to NMSCs. The two most widely used topical agents for the treatment of multiple AKs are 5- fluorouracil (5-FU) and imiquimod. Although visits for AKs accounts for over 3.7 million ambulatory care office visits per year in the US and their treatment poses a substantial financial burden to our healthcare system, costing over a billion dollars annually, no studies have compared the effectiveness of the these twp topical field-based therapies. We propose to compare the effectiveness of 5-FU and imiquimod in preventing NMSCs (primary aim) and AKs (secondary aim) using retrospective data from Kaiser Permanente Northern California (KPNC). We also seek to ascertain dose-response curves for each drug over a 5 year follow-up period. One of the unique features of the project is the setting, which allows for ascertainment of effectiveness in a real-world practice environment. KPNC also offers the added advantage of rich electronic databases, with a wealth of information of exposure (detailed pharmacy database), outcome (unique NMSC registry which identified non-reportable skin cancer), and potentially relevant co-variates. The other unique aspect of this proposal is the way in which the retrospective observational data is approached, utilizing novel biostatistical methodologies (point-treatment marginal structural models) to draw casual inference regarding the relationship between exposure and outcome as would be obtained in a clinical trial setting. These newly developed methods have not been previously used in Dermato-epidemiology. The goals of this project align with NIAMS's long-range planning goals of increasing skin related clinical research by performing comparative effectiveness of therapies, and combination therapy approaches for skin disease treatment. By accomplishing our study aims, we can help identify the most effective topical agent among high risk individuals for the prevention of the most common cancer in America.